Mucosal surfaces, such as the respiratory epithelium, are directly exposed to the external environment and therefore, are highly susceptible to viral infection. As a result, the respiratory tract has evolved a variety of innate and adaptive immune defenses in order to prevent viral infection or promote the rapid destruction of infected cells and facilitate the clearance of the infecting virus. Successful adaptive immune responses often lead to a functional state of immune memory, in which memory lymphocytes and circulating antibodies entirely prevent or lessen the severity of subsequent infections with the same virus. This is also the goal of vaccination, although it is difficult to vaccinate in a way that mimics respiratory infection. Consequently, some vaccines lead to robust systemic immune responses, but relatively poor mucosal immune responses that protect the respiratory tract. In addition, adaptive immunity is not without its drawbacks, as overly robust inflammatory responses may lead to lung damage and impair gas exchange or exacerbate other conditions, such as asthma or chronic obstructive pulmonary disease (COPD). Thus, immune responses to respiratory viral infections must be strong enough to eliminate infection, but also have mechanisms to limit damage and promote tissue repair in order to maintain pulmonary homeostasis. Here, we will discuss the components of the adaptive immune system that defend the host against respiratory viral infections.

Introduction

The respiratory tract is susceptible to a variety of pulmonary viruses, including among others, influenza viruses, respiratory syncytial virus (RSV), rhinoviruses, parainfluenza viruses, metapneumovirus, adenoviruses, and coronaviruses [1]. Depending on the strain, these viruses can cause symptoms that range from mild sinusitis, tonsillitis, and laryngitis to more severe bronchitis, pneumonia, and even death. Approximately 200 million cases of viral pneumonia occur each year throughout the world [2], resulting in significant morbidity and mortality. Moreover, respiratory virus infections also contribute to secondary bacterial pneumonia [2], another significant cause of morbidity and mortality. As a result, respiratory viral infections have an enormous economic impact, both in terms of healthcare costs and lost productivity [3,4].

Some respiratory viruses cause more severe illness or more commonly affect certain age groups. For example, RSV is the most common cause of pulmonary disease in children under 2 years of age [5], in whom it is associated with bronchiolitis, pneumonia, bronchitis and, over the long-term, may contribute to the development of asthma-like symptoms [6]. Similarly, parainfluenza viruses are a major cause of croup in young children [7,8], and can cause bronchitis, pneumonia, and bronchiolitis. Influenza viruses are also a significant cause of yearly seasonal epidemics and, upon occasion, worldwide pandemics [9]. Children, elderly, and individuals with comorbidities are more severely affected by seasonal influenza infections, whereas otherwise healthy young adults often bear the brunt of pandemic influenza infections [10]. Adenoviruses cause pulmonary symptoms from pharyngitis to pneumonia and may infect other mucosal sites [1]. Rhinoviruses, metapneumovirus, and coronaviruses are typically associated with symptoms of the common cold, although coronaviruses like sudden acute respiratory syndrome corona virus (SARS-CoV) and Middle East respiratory syndrome corona virus (MERS-CoV) are associated with severe respiratory distress and mortality [11,12]. All of these viruses are associated with the exacerbation of preexisting lung conditions, such as asthma and chronic obstructive pulmonary disease (COPD) [13].

The symptoms caused by respiratory viruses are largely overlapping, making a definitive diagnosis difficult. Moreover, antiviral drugs are limited in number and are mostly restricted to influenza viruses. Thus, most viral infections are treated non-specifically in order to relieve symptoms. Nevertheless, some drugs are available, including amantadine and rimantadine, which block the influenza matrix-2 (M2) ion channel [14], and oseltamivir and zanamivir, which inhibit the function of influenza neuraminidase (NA) [14]. Unfortunately, seasonal influenza viruses evolve rapidly and many strains are already resistant to the available drugs [15,16]. Thus, the development of new antiviral drugs is an urgent global health priority.

Given the impact of respiratory virus infections and the lack of good antiviral agents, the development of prophylactic vaccines against the most common respiratory viruses would be a major benefit. In fact, vaccination is one of the most successful public health measures ever taken [17], particularly for viruses like smallpox. However, the maximization of both safety and effectiveness is sometimes difficult. For example, the oral polio vaccine is administered as an attenuated virus and elicits long-lasting systemic and mucosal immune responses. However, it is associated with paralytic poliomyelitis in about three per million recipients. In contrast, the inactivated polio vaccine elicits a serum IgG response, but fails to prevent infection at mucosal sites, which is its preferred route of entry [18]. Thus, it is important to develop vaccines that elicit beneficial immune responses in the right location. In an extreme example of how vaccine development can go wrong, the initial efforts to develop a vaccine against RSV foundered when vaccinated children developed exacerbated immunopathology in response to infection [19]. Thus, a robust, vaccine-induced immune response can backfire when it fails to control infection.

Although vaccination can be highly effective, vaccines against many respiratory viruses have remained elusive. In part, this lack can be attributed to mechanisms by which viruses have evolved to evade the immune system, particularly antibody-mediated immunity. For example, although adaptive immune responses can successfully clear infections with rhinovirus and RSV [20,21], the development of a neutralizing antibody response (the hallmark of vaccine-mediated protection) is very poor [22,23]. As a result, individuals are often reinfected with rhinovirus or RSV [24,25], despite having previously generated a successful adaptive immune response. This same problem is encountered in vaccination against these viruses. In contrast, immunity to influenza virus is easily elicited by either infection or vaccination [26,27]. However, the influenza virus mutates so rapidly that vaccines must be reformulated every year to account for changes in the viral hemagglutinin (HA) [28]. Therefore, in order to develop more effective or more broadly applicable vaccines, it is instructive to understand how the immune system responds to (or is subverted by) various respiratory viruses.

Anatomy of pulmonary immune responses

The respiratory tract can be divided into the nose, nasal passages, sinuses, pharynx, and larynx of the upper respiratory tract and the trachea, bronchi, bronchioles, and alveoli of the lower respiratory tract (Figure 1). Each of these locations is exposed to different types of environmental stimuli, has distinct structures, and is protected by slightly different immune mechanisms that are regulated by a variety of local lymphoid tissues. For example, immune responses in the upper respiratory tract are directed by the superficial and deep cervical lymph nodes (LNs), as well as the submucosal lymphoid tissues of Waldeyer’s ring (palatine tonsils, adenoids, lingual tonsil, and tubal tonsil) and the nasal-associated lymphoid tissue (NALT). Similarly, immune responses in the lower respiratory tract are directed by the mediastinal and hilar LNs and by bronchus-associated lymphoid tissues (BALT)—see Figure 2. Interestingly, although BALT functions like a secondary lymphoid tissue [29], it is not present in the lungs of immunologically naïve humans or mice [30]. Instead, inducible BALT (iBALT) forms following pulmonary inflammation, often during the neonatal period [31]. Thus, iBALT is best considered a tertiary or ectopic lymphoid tissue [32].

Schematic of the respiratory tract and associated lymphoid tissues

Figure 1
Schematic of the respiratory tract and associated lymphoid tissues

The respiratory tract is divided into the upper respiratory tract, which begins at the nostrils and extends to the trachea, and the lower respiratory tract, which begins at the trachea and extends to the alveolar spaces of the lung. Lymphoid tissues include encapsulated LNs and mucosal lymphoid tissues like the NALT, adenoids, tonsils, and BALT.

Figure 1
Schematic of the respiratory tract and associated lymphoid tissues

The respiratory tract is divided into the upper respiratory tract, which begins at the nostrils and extends to the trachea, and the lower respiratory tract, which begins at the trachea and extends to the alveolar spaces of the lung. Lymphoid tissues include encapsulated LNs and mucosal lymphoid tissues like the NALT, adenoids, tonsils, and BALT.

Schematic of BALT

Figure 2
Schematic of BALT

Mucosal lymphoid tissues, including BALT, NALT, tonsils, and adenoids, are not encapsulated. Instead leukocytes are clustered directly beneath the mucosal epithelium. The mucosal epithelium that overlays a lymphoid tissue contains specialized microfold (M) cells, which transport antigens, particulates, and even pathogens across the epithelium. Dendritic cells (DCs) are positioned directly beneath the epithelium, where they can collect incoming antigens. B-cell follicles are positioned beneath the DC layer. T cells are located in the interfollicular areas and surrounding the B-cell follicles. Efferent lymphatic vessels are found at the edge of the T-cell area and collect fluids and cells from the tissue and carry them to downstream LNs or into the blood.

Figure 2
Schematic of BALT

Mucosal lymphoid tissues, including BALT, NALT, tonsils, and adenoids, are not encapsulated. Instead leukocytes are clustered directly beneath the mucosal epithelium. The mucosal epithelium that overlays a lymphoid tissue contains specialized microfold (M) cells, which transport antigens, particulates, and even pathogens across the epithelium. Dendritic cells (DCs) are positioned directly beneath the epithelium, where they can collect incoming antigens. B-cell follicles are positioned beneath the DC layer. T cells are located in the interfollicular areas and surrounding the B-cell follicles. Efferent lymphatic vessels are found at the edge of the T-cell area and collect fluids and cells from the tissue and carry them to downstream LNs or into the blood.

Pulmonary immune responses begin with the innate recognition of viral infection. This recognition initially occurs within infected cells, which detect virus-derived nucleic acids and respond by secreting type I interferon (IFN) and expressing antiviral defense genes [33,34]. Cells killed by viruses also release damage-associated molecules [35], which together with type I IFN and other inflammatory cytokines [36] activate innate cells like macrophages and DCs and call in additional inflammatory cells from the circulation [37]. DCs also take up antigens from virally infected cells, migrate to the lymphoid tissues and present antigens to naïve B and T cells [38–40]. Those B and T cells that recognize viral antigens become activated, proliferate rapidly over the next few days and eventually differentiate into effector cells that migrate through the blood to the site of infection, where they perform their effector functions. For example, some B cells may differentiate into short-lived plasmablasts that home to the nasal and pulmonary mucosa and secrete antibody [41,42], whereas other B cells will differentiate into long-lived plasma cells that home to the bone marrow and secrete antibody for decades [43]. Some CD4+ T cells will likely differentiate into cytokine producing effector cells that home to the lung and promote macrophage activation and inflammatory cell recruitment [44], whereas other CD4+ T cells will differentiate into T follicular helper (Tfh) cells that remain in lymphoid tissues and provide help to B cells [45]. CD8+ T cells primarily differentiate into cytolytic effector T cells (CTLs) that kill virally infected cells [46]. Once virus is cleared, most of the responding B and T cells will die by apoptosis, leaving a few resting memory cells in both the respiratory tract and in lymphoid organs [47], where they will await their next encounter with the same antigen. These steps are diagrammed schematically in Figure 3.

Kinetics and magnitude of immune response components

Figure 3
Kinetics and magnitude of immune response components

The immune response is divided temporally into the primary response of an immunologically naïve individual (left) and a secondary response in an immunologically experienced individual (right). The x-axis (time) is not to scale, as pulmonary infections may last about a week, whereas memory cells or antibodies can be maintained for decades. Green lines indicate the viral load. Note that viral load is reduced in a secondary response. Black lines indicate the innate response to viral infection, which mirrors viral load. Violet lines indicate the response of virus-specific B and T cells, which in the naïve state are nearly undetectable, at the peak of infection may comprise up to 30% of the total cells in the lung, and in the resting memory state are relatively low (less than 1%), but at a much higher frequency than in naïve individuals. The red line indicates virus-specific serum antibody levels, which increase rapidly following a primary immune response and (in most cases) can be maintained at very high levels.

Figure 3
Kinetics and magnitude of immune response components

The immune response is divided temporally into the primary response of an immunologically naïve individual (left) and a secondary response in an immunologically experienced individual (right). The x-axis (time) is not to scale, as pulmonary infections may last about a week, whereas memory cells or antibodies can be maintained for decades. Green lines indicate the viral load. Note that viral load is reduced in a secondary response. Black lines indicate the innate response to viral infection, which mirrors viral load. Violet lines indicate the response of virus-specific B and T cells, which in the naïve state are nearly undetectable, at the peak of infection may comprise up to 30% of the total cells in the lung, and in the resting memory state are relatively low (less than 1%), but at a much higher frequency than in naïve individuals. The red line indicates virus-specific serum antibody levels, which increase rapidly following a primary immune response and (in most cases) can be maintained at very high levels.

Importantly, the primary adaptive immune response to any particular virus is slower and generally of a lower magnitude than a secondary response to virus. In part, this is because the precursor frequency of naïve B or T cell specific for any particular viral antigen is very low [48,49]. However, in a secondary response, the precursor frequency of memory B and T cells is much higher (Figure 3) [50]. Moreover, memory B and T cells have already been programmed for a rapid response and many of them are already placed in the respiratory tract [51–54]. Together, the higher frequency of starting cells, their predifferentiated state and their proximity to antigen make the secondary immune response much more rapid and effective than a primary response (Figure 3). In addition, if neutralizing antibodies are generated during the primary response, long-lived plasma cells in the bone marrow will produce these antibodies for decades [43], leading to high titers in the serum that may completely prevent secondary infection.

Although most primary B- and T-cell responses are initiated in lymphoid tissues, such as LNs or submucosal lymphoid tissues, these tissues are architecturally and functionally distinct. For example, LNs are encapsulated lymphoid organs that collect antigens and cells through lymphatic vessels from distal sites [55,56], such as the lung, whereas the submucosal lymphoid organs like NALT and BALT collect antigens directly across a specialized mucosal epithelium via microfold (M) cells (Figure 2) [57,58]. Regional lymphoid organs also tailor immune responses to the tissues from which they collect antigens, in part because the different types of DCs, in each tissue, imprint unique characteristics on immune responses to antigens from each location [59–61]. For example, the submucosal lymphoid tissues of the upper respiratory tract bias their B-cell responses toward the production of IgA at the expense of IgG [62,63]. In contrast, the lymphoid tissues of the lower respiratory tract often produce more IgG and less IgA [62]. This difference makes sense when considering how antibodies are delivered to the upper and lower respiratory tracts. The thicker, pseudostratified epithelium of the upper respiratory tract is best protected by IgA [62], which is transported across the epithelium via the polymeric Ig-receptor (pIgR) [64]. In contrast, the lower respiratory tract, particularly the alveolar spaces, is best protected by IgG [62], which is delivered by transudation across the thin membrane between alveolar capillaries and alveolar epithelium. Thus, the functions of regional lymphoid organs are specialized to produce B and T cells that best protect the tissues from which they collect antigens.

Innate immunity

The respiratory epithelium lining the trachea and bronchi is covered by a liquid layer of mucus that traps inhaled particulates and pathogens, including viruses [65]. This mucus layer is continuously propelled upward by the movement of cilia, leading to the mechanical clearance of any trapped particles or pathogens. In addition, bioactive molecules in the mucus layer target pathogens directly or promote their clearance by opsonization or the recruitment of inflammatory cells. For example, lactoferrin can hydrolyze RNA [66,67] and is therefore important against some types of RNA viruses [68]. In addition, although defensins are most often associated with anti-bacterial activity [69], they are also reactive against enveloped and non-enveloped viruses [70–72]. Similarly, the family of collectins, including surfactant proteins A and D (SP-A and SP-D) and mannan-binding lectin (MBL), bind to carbohydrates on the surface of some viruses [73], thereby triggering the alternate complement cascade [74], and promoting viral opsonization and recruiting inflammatory cells. Together, these activities form the first line of defense against viral infection.

Airway epithelial cells are also an important source of inflammatory cytokines and chemokines following direct viral infection [75,76] or the detection of pathogen-associated molecular patterns (PAMPs) [77] or damage-associated molecular patterns (DAMPs) [78] via toll-like receptors (TLRs) and other receptors [79]. For example, virus-infected epithelial cells produce type I IFNs, which directly interfere with viral replication [80], trigger an antiviral state in surrounding cells [81,82], and promote the activation and differentiation of innate and adaptive immune cells. Epithelial cells are potent producers of type I IFN following infection with RSV and influenza viruses [83]. Epithelial cells also produce inflammatory cytokines like interleukin (IL)-6 and RANTES [79], which also facilitate the recruitment and activation of both innate and adaptive cells.

Unlike the respiratory epithelium, the alveolar epithelium is not ciliated and lacks mucus due to the requirement for gas exchange. As a result, the alveolar epithelial cells rely on their own intracellular defenses [75,76]. In fact, all cells, including alveolar and respiratory epithelial cells, have intracellular pathogen recognition receptors that sense viral nucleic acids or replication intermediates and either directly interfere with viral replication or trigger the expression of antiviral genes [82]. For example, the RIG-I and MDA5 molecules recognize various forms of intracellular viral RNA and act through MAVS to induce an intracellular antiviral state [84]. Similarly, STING is involved in the intracellular sensing of viral DNA [85]. One of the primary outcomes following the intracellular recognition of viral infection is the production of type I IFN [86], which binds to the IFNa receptor on infected cells as well as neighboring cells and induces the expression of antiviral genes [81,86], triggers apoptosis [82], and shuts down protein synthesis [81,87] in order to limit the spread of infection.

Given the importance of intracellular viral sensing mechanisms and the resulting IFN responses, it is not surprising that respiratory viruses have developed mechanisms to subvert detection or to inactivate the type I IFN response. For example, influenza virus uses the non-structural-1 (NS-1) protein to impair the function of RIG-I [88,89]. Similarly, RSV uses NS2 [90], whereas coronavirus uses M protein [91] and picornaviruses like rhinovirus (type 1a and 16) uses proteinases to cleave RIG-I [92]. In each of these cases, the virus is attempting to subvert the intracellular antiviral machinery, prevent, or delay the production of type I IFN in order to successfully replicate and infect additional cells or individuals.

Phagocytic cells, including alveolar macrophages (AMs), DCs, and neutrophils, are also an important component of innate defense in the lung. AMs are a lung-resident population of macrophages derived from fetal monocytes that differentiate in response to the cytokine GM-CSF [93] and the transcription factor PPARγ [94,95]. Under steady-state conditions, AMs phagocytose inhaled particulates or pathogens and degrade them without triggering inflammation or adaptive immunity [96]. In the context of viral infection, AMs facilitate viral clearance by complement activation, phagocytosis, the production of inflammatory mediators, and the recruitment of neutrophils [97,98]. In addition to their antiviral functions, AMs reduce the severity of immune-mediated lung damage by suppressing inflammation [96,99,100] and promoting airway repair [101]. Although neutrophils are often associated with pulmonary damage, the depletion of neutrophils in influenza-infected mice leads to enhanced morbidity and mortality, as well as increased viral loads [97,102–105]. Interestingly, neutrophils do not facilitate viral clearance on their own, but enhance CD8+ T-cell responses by leaving trails of CXCL12, which are followed by CXCR4-expressing T cells [106].

DCs are also found in the respiratory tract and lymphoid organs under steady-state conditions and are well characterized in the context of respiratory virus infections [107,108]. Conventional DCs in lymphoid organs are divided into resident (rDCs) and migratory DCs (mDCs) [40,109,110]. The rDCs in lymphoid organs differentiate locally from blood-derived precursors, whereas mDCs differentiate in peripheral tissues like the lung, and upon activation, up-regulate CCR7 [111] and migrate via afferent lymphatic vessels into draining LNs, where they present antigen to naïve T cells [40].

The mDCs in non-inflamed lungs include the CD103+CD11blo DCs, which are found in the pulmonary epithelium [112] and CD103CD11bhi cells [107], which are found in the lung parenchyma. These two subsets have different developmental origins, as CD103+CD11blo DCs require the transcription factors Batf3 and IRF8, and are dependent on Flt3 ligand [113,114], whereas CD103CD11bhi DCs develop independently of Batf3 or IRF8 and require M-CSF [115]. Importantly, the CD103+CD11blo DCs preferentially acquire exogenous antigens, such as dead or apoptotic cells [116], and present those antigens in the MHC class I pathway to CD8 T cells—a process known as cross-priming [117]. Thus, these cells are of central importance in initiating CD8 T-cell responses to viruses [114].

The CD103+CD11blo cells are the first to respond to pulmonary virus infection and rapidly traffic to the LNs [118]. Some studies suggest that migratory DCs do not directly present antigen to T cells, but deliver antigen to rDCs in the LNs [119]. However, other studies suggest that mDCs carry antigen from the lung and directly present antigens to T cells [40]. Interestingly, CD103+CD11blo DCs seem to dominate the early phase of antigen presentation in the LNs, but are much less important at later times, because they are initially depleted from the lungs and are slowly replenished [40]. In contrast, the CD103CD11bhi DCs continue to accumulate in the lung and LN following viral infection and dominate the presentation of antigen to CD8+ T cells at later times [40,107].

Pulmonary infection also leads to the recruitment of monocyte-derived DCs (Mo-DCs) in the LN. These cells are also termed inflammatory DCs due to their robust production of TNF and IL-12 [120,121]. A similar population of CD103CD11bhi DCs is also recruited to the lungs following inflammation [122,123]. Compared with conventional CD103CD11bhi DCs in steady state, CD103CD11bhi Mo-DCs express high levels of Ly6C, CD64, and the high-affinity IgE receptor (FcεR1) [123]. Mo-DCs are rapidly recruited to the lung during viral infection and, in turn, facilitate the recruitment and further activation of CD8+ T cells [124]. Thus, Mo-DCs primarily affect CD8+ T-cell activation in the respiratory tract rather than the LN [125,126]. Given their production of inflammatory cytokines and nitric oxide, it is not too surprising that Mo-DCs can also be associated with pulmonary damage following respiratory infections [127].

Plasmacytoid DCs (pDCs) also reside in the lung and use TLR7 to detect viral RNA [128]. Although their role in antigen presentation and T-cell activation is controversial [129], virus-activated pDCs are potent sources of type I IFN [130]. The IFN produced by pDCs and epithelial cells is important for the activation of conventional DCs [131], the expansion of CD8+ T cells, the polarization of CD4+ T cells to Th1 cells [132], and the differentiation of virus-specific B cells [133]. Thus, pDCs are an important component of the innate response that helps shape the adaptive immune response to pulmonary viruses.

Adaptive immunity—CD8+ T cells

T cells are broadly divided into CD4+ ‘helper’ T cells and CD8+ ‘killer’ T cells. CD8+ T cells differentiate into cytotoxic T cells (CTLs) that produce cytokines and effector molecules that impair viral replication and kill virus-infected cells. Thus, they are essential for the clearance of most pulmonary viruses [134 ] - see Table 1. For example, CD8+ T cells are essential for clearing influenza virus during a primary infection [135]. Moreover, although neutralizing antibodies can completely prevent a second infection with the same serotype of influenza, CD8+ T cells specific for epitopes in conserved influenza proteins, such as nucleoprotein (NP) [136,137], are very important for responses to different influenza serotypes and subtypes—so-called heterosubtypic immunity [138]. The CTL response is also important for the clearance of both primary and secondary infections with RSV [21], coronaviruses [139], adenoviruses [140,141], and parainfluenza viruses [142].

Table 1

Characteristics of immunity to respiratory viruses

Virus Neutralizing antibody Beneficial antibodies Long-lived antibody Antibody evasion Protective CD8/CTL Protective CD4/Th Pathogenic CD4/Th 
Influenza Strong HA [26,54,403M2e [405,15,403,353Yes [26,406Serotype drift [393,392,407CTL [26,135,403,136,138,408, 155,158,409Th1 [26,183185,193,214, 286,403,410,411Th2 [415
 Weak NA [404NP [320,351 Subtype shift [393,392,407TRM [51,272,303TRM [412 
  M1 [352   Tfh [176,413,414,286 
RSV F protein [321,322,416Poor M2 [322,416Poor [23,391Serotype drift—insignificant [417CTL [21,221Th1 [221,224Th2 [219,225,226, 378,418
 G protein [322,416Poor N [322,416 Subtype shift—insignificant [417TRM [299TRM [300 
      Tfh [391 
Rhinovirus Strong VP1–3 [419,420 Poor [22Serotype drift [421,422CTL [20,422Th1 [20,422,423,424Th2 [220
    Subtype shift—none TRM TRM  
      Tfh  
Coronavirus Strong S protein [323,389 Poor [390Serotype drift [425CTL [139,166Th1 [390,429Th2 
    Subtype shift [426,427,428TRM [139,429TRM [429 
      Tfh [429 
Parainfluenza Strong F and H–N protein [325 Yes [430,431Serotype drift [393CTL [142Th1 [433,434,283Th2 [434
   Poor—in infants [432Subtype shift TRM [272TRM [53 
      Tfh  
Virus Neutralizing antibody Beneficial antibodies Long-lived antibody Antibody evasion Protective CD8/CTL Protective CD4/Th Pathogenic CD4/Th 
Influenza Strong HA [26,54,403M2e [405,15,403,353Yes [26,406Serotype drift [393,392,407CTL [26,135,403,136,138,408, 155,158,409Th1 [26,183185,193,214, 286,403,410,411Th2 [415
 Weak NA [404NP [320,351 Subtype shift [393,392,407TRM [51,272,303TRM [412 
  M1 [352   Tfh [176,413,414,286 
RSV F protein [321,322,416Poor M2 [322,416Poor [23,391Serotype drift—insignificant [417CTL [21,221Th1 [221,224Th2 [219,225,226, 378,418
 G protein [322,416Poor N [322,416 Subtype shift—insignificant [417TRM [299TRM [300 
      Tfh [391 
Rhinovirus Strong VP1–3 [419,420 Poor [22Serotype drift [421,422CTL [20,422Th1 [20,422,423,424Th2 [220
    Subtype shift—none TRM TRM  
      Tfh  
Coronavirus Strong S protein [323,389 Poor [390Serotype drift [425CTL [139,166Th1 [390,429Th2 
    Subtype shift [426,427,428TRM [139,429TRM [429 
      Tfh [429 
Parainfluenza Strong F and H–N protein [325 Yes [430,431Serotype drift [393CTL [142Th1 [433,434,283Th2 [434
   Poor—in infants [432Subtype shift TRM [272TRM [53 
      Tfh  

Naive CD8+ T cells are initially activated by antigen-bearing DCs that migrate from the lung to the T-cell zone of the LN [119], where they promote T-cell proliferation and differentiation—a process that is enhanced by type I IFN and IL-12, which are produced by virus-activated innate cells like DCs [143]. Epithelial cells also facilitate the recruitment, local expansion, and differentiation of lymphocytes in the lung via the production of inflammatory cytokines and chemokines [79]. Moreover, the differentiation of CD8+ T cells is also guided by IL-2 [144] and IFNγ [145], which are produced by T cells, including the CD8+ T cells themselves.

The initial activation of CD8+ T cells is facilitated by the classic costimulatory molecule, CD28 [146], and at later times, the survival or local expansion of CD8+ T cells is enhanced by the engagement of other costimulatory molecules, such as the TNFR family members, 4-1BB and CD27 [147,148]. Interestingly, although costimulatory ligands are typically associated with APCs like DCs, B cells, and macrophages, epithelial cells also express molecules like 4-1BB and PD-L1 [149,150], which together with antigen modulate the magnitude of the CD8+ T-cell response and the differentiation program of the responding cells.

Following activation and differentiation in a lymphoid tissue, CTLs down-regulate CCR7 and up-regulate receptors like CXCR3 and CCR4, which promote their recruitment to the lung [151], where they encounter and kill virus-infected cells. Killing occurs during a cognate encounter between CTLs and their virus-infected targets, which triggers the release of cytotoxic granules that contain molecules like perforin and granzymes [152]. Perforin is a protein that embeds into the membrane of target cells, form pores that directly promote target killing, and allow the entry of granzymes, which cleave caspases in the target cell and promote apoptosis [153]. CTLs also express cytokines, such as TNF, FASL, and TRAIL [154–156], which engage death receptors on target cells and promote apoptosis [157,158]. Finally, CTLs are potent producers of the antiviral cytokine, IFNγ [159,160], which activates inflammatory cells like macrophages [161] and promotes antiviral gene expression in surrounding cells [162]. The importance of IFNγ in antiviral immunity is highlighted by the various mechanisms used by viruses to evade its function [163,164]. Finally, although the inflammatory and cytolytic activities of CTLs contribute to pulmonary damage, CD8+ T cells also produce IL-10 [165–167], which tempers the inflammatory response.

Depending on the amount and duration of antigen, inflammatory signals and costimulatory ligands, virus-specific CD8+ T cells differentiate into short-lived effector cells (SLECs) or memory precursor effector cells (MPECs), which are distinguished by their expression of KLRG1 and CD127 [168]. KLRG1+CD127CD8+ T cells are SLECs, whereas KLRG1CD127+CD8+ T cells are MPECs [169]. SLECs perform their required effector function and rapidly undergo apoptosis when antigen (virus) is cleared [169]. This phenomenon is observed as a notable contraction of the overall CD8+ T-cell response (Figure 3). In contrast, MPECs are the precursors that seed the long-lived pool of memory CD8+ T cells. These differential cell fates are governed by the balance of transcription factors in the responding CD8+ T cells—higher expression of Bcl-6 [170], IL-6 [171], and Id3 [172] favor the development of MPECs, whereas Id2 [173], T-bet [169], and BLIMP-1 [174] favor the differentiation SLECs. Importantly, Bcl-6 and BLIMP-1 counter-regulate one another [175]. Thus, fine-tuning this balance is critical for the regulation of the CD8+ T-cell response.

Adaptive immunity—CD4 T cells

CD4+ T cells are also important for resistance to respiratory virus infection [53 ] - see Table 1. CD4+ T cells are essential for the differentiation of antibody-producing B cells [176,177], the activation of virus-specific CD8+ T cells [178–180], the local activation of AMs [181], and the recruitment of inflammatory cells into the lung [182]. In fact, resistance to a variety of viruses, including influenza, is compromised in the absence of CD4+ T cells [183,184], even though the activities of CD8+ T cells and T cell-independent antibodies can mediate delayed viral clearance in many cases [185]. Nevertheless, long-term antibody responses are completely dependent on help from CD4+ T cells [186], meaning that successful vaccination requires a functional CD4+ T-cell compartment.

Like CD8+ T cells, CD4+ T cells responding to respiratory virus infection are activated by DCs that migrate from the lung to the draining LN [187,188]. Antigen, costimulatory molecules, and cytokines made by DCs, epithelial cells, and inflammatory cells dictate how the responding CD4+ T cells differentiate. For example, CD4+ T cells responding to respiratory virus infections are typically stimulated by the innate cytokines, IL-12 and type I IFN [189,190], which promote the expression of the transcription factor, T-bet [191], and direct the differentiation of Th1 cells [192]. Th1 cells express the antiviral cytokine, IFNγ, as well as TNF and IL-2 [192]. IFNγ, made as an autocrine factor by the CD4+ T cells themselves [193] or by innately activated macrophages and DCs [194,195], also helps to polarize Th1 cells [196]. Th1 effector CD4+ T cells activate AMs and promote antiviral gene expression via IFNγ production [197,198], recruit inflammatory cells via the expression of chemokines [199,200], and help CD8+ T-cell activation and expansion by providing IL-2 and IFNγ [201,202].

In fact, CD4+ T cells are a potent source of help to CD8+ T cells [203]. This help can be indirect, in which Th1 cells activate (license) DCs by providing costimulation in the form of CD40 ligand (CD40L) [204–206]. CD40 signaling on DCs and monocytes potently up-regulates IL-12 [207,208], which facilitates CD8+ T-cell differentiation. CD4+ T cells may also help CD8+ T cell directly via CD40L: CD40 signaling [209], similar to how they help B cells [210], although other studies suggest that this pathway rarely occurs [211,212]. Additionally, CD4+ T cells provide help to CD8+ T cells in the form of cytokines like IL-2 and IFNγ [210,213]. Thus, CD4+ T cell helps to enhance most CD8+ T-cell responses to respiratory viruses.

CD4+ T cells are typically described as helpers. However, under some circumstances, they can also differentiate into killers [214]. For example, in the context of influenza infection, CD4+ T cells can be hyperpolarized by IL-2 and antigen and differentiate into cells that express perforin and granzyme B [215], molecules typically associated with CTLs. Importantly, these CD4+ cells can lyse target cells that present antigenic peptides in MHCII molecule [184], and facilitate the clearance of a pulmonary influenza infection [184]. Thus, CD4+ T cells play many different roles in resistance to respiratory viruses [214].

Although Th1 cells are potent effector cells against respiratory viruses [216], CD4+ T cells have a variety of alternative cell fates, including Th2, Th17, Treg, and Tfh [217]. Th2 cells rely on the transcription factor GATA3 [218], produce IL-4, IL-5, and IL-13 and are typically associated with allergic responses or parasite infections. Surprisingly, some respiratory viruses also elicit Th2 responses [219], which fail to control viral replication and instead lead to pulmonary inflammation [21,220]. For example, although pulmonary infection with RSV does elicit protective Th1 and CTL responses [221], it also promotes the differentiation of Th2 cells that make IL-4, IL-5, and IL-13 recruit eosinophils to the lung and promote pulmonary damage [222,223]. Interestingly, the F protein of RSV skews CD4+ T-cell differentiation toward a Th1 response [224], whereas the G protein skews it toward a Th2 response [225]. This effect is also important in the context of vaccination, as observed in early trials of an RSV vaccine that elicited potent Th2 immunity that failed to control infection and instead promoted Th2-driven inflammation [226]. Taken together, it seems clear that the expression of type 2 cytokines in the context of respiratory viruses is associated with inflammation and damage rather than protective immunity.

Th17 cells, which rely on the transcription factor, RORγt [227], produce IL-17 and IL-22 [227] and recruit neutrophils [228], are also not typically associated with viral infection. However, IL-17 can be observed in both humans and mice infected with RSV [229,230]. Not surprisingly, the expression of IL-17 in the context of RSV infection is associated with an influx of neutrophils, increased airway hyperreactivity, and generally worse outcomes [229]. Moreover, IL-17 also reduces CD8+ T-cell activity by binding to IL-17R on CD8+ T cells [230]. Thus, IL-17 promotes inflammation and impairs productive immunity. Importantly, DCs from infants are poor producers of IL-12 [231], which promotes Th1 responses [232], but better producers of TGFβ [233], which helps Th17 responses [234], suggesting that infants may be particularly susceptible to Th17 responses following RSV infections. Together, these data suggest that like Th2 cells, Th17 cells contribute to pulmonary inflammation in the context of respiratory virus infections.

CD4+ T cells that provide help to B cells are known as Tfh cells [235]. Tfh cells are phenotypically identified by their expression of the chemokine receptor, CXCR5 [236,237], the inhibitory receptor, programmed death-1 (PD-1) [238,239], the costimulatory molecule, inducible T-cell costimulator (ICOS) [240,241], CD40L and the cytokine, IL-21 [242,243]. The signature transcription factor of Tfh cells is Bcl-6 [244–246], a zinc finger protein that represses the expression of BLIMP-1 and thereby prevents differentiation toward a Th1 phenotype [244].

Although Tfh cells are primarily found in the B-cell follicles of secondary lymphoid organs, they can also be found in some peripheral non-lymphoid tissues like the lung [176]. These Tfh cells likely reside in iBALT structures that form following pulmonary infection [31], and appear in the lung following infection, at the same time as B cells with a GC phenotype [176]. In contrast, mice sensitized to pulmonary allergens have B cells with a GC phenotype in their lungs [247], but lack well-defined iBALT areas or conventional Tfh cells. Instead, these mice have IL-21-producing CD4+ T cells that have B-cell helper activity, but lack CXCR5 and Bcl-6 [247]. These data suggest that the pulmonary environment may support CD4+ effector T cells with some properties of Tfh that facilitate local B-cell activation in non-lymphoid tissues [247].

A final population of CD4+ T cells is the regulatory (Treg) cells [248], which depend on the transcription factor, FOXP3 [249], and make anti-inflammatory cytokines like IL-10, TGFβ, and IL-35 [250]. Unlike the other subsets of Th cells, which promote various types of immune responses, Tregs inhibit immune responses [248,250]. A primary function of Tregs is to limit autoimmunity by suppressing any autoreactive T cells that made it through the thymus without getting deleted—a process known as peripheral tolerance [251]. However, Tregs also dampen immune responses to infection [252,253] and promote the resolution of immune responses in order to prevent immunopathology [254–257]. Tregs accomplish these goals by a variety of mechanisms, including IL-10 [258], TGFβ [259], and amphiregulin [260], which are potent anti-inflammatory cytokines that act on both B and T cells [261].

Given that a strong immune response is generally necessary for eliminating respiratory viruses, there must be mechanisms for temporarily suppressing Treg activity. In fact, the inflammatory cytokine, IL-6 impairs Treg activity [262,263] as does type I IFN [264,265]. Thus, during acute viral infection of the lung, these cytokines activate DCs [266], promote effector T-cell differentiation [267,268], and impair Treg activity. However, the copious amounts of IL-2 produced by effector cells during the adaptive immune response expands the numbers of Tregs and promotes their activity [269], which then dampens the adaptive immune responses and promotes resolution of the immune response [270]. Thus, the activity of effector and regulatory T cells is temporally controlled during infections with respiratory viruses.

Memory T cells

Following a primary infection, the vast majority of effector T cells die by apoptosis [271], leaving a much smaller population of memory T cells [272]. Despite the contraction of the acute T-cell response, memory T cells persist for long periods at much higher frequencies than naïve T cells [48]. In fact, some of these memory T cells have stem cell-like qualities that allow their self-renewal [273]. Importantly, memory T cells are imprinted for specific effector functions [274] and are transcriptionally and metabolically poised to rapidly produce effector molecules following encounter with antigen [275–277]. In addition, many memory cells have altered their homing and adhesion molecules such that they recirculate through or reside in non-lymphoid tissues as permanent residents [278,279]. Together, these properties of memory cells allow for a faster response to antigen in the most appropriate location, which results in faster clearance of virus and less pulmonary damage [139,280].

In mice, influenza-specific memory CD8+ T cells can persist for life—approximately 2 years [281], whereas in humans, they can persist for at least 13 years [282]. Similarly, Sendai virus-specific memory CD4+ T cells persist in the lung airways and parenchyma for approximately 3 months after infection [283]. Interestingly, the number of memory CD4+ T cells is often lower than the number of memory CD8+ T cells [283,284]. In fact, unlike memory CD8+ T cells, which are maintained at stable numbers following the contraction phase, memory CD4+ T cells continue to decline and become undetectable in a few months [283]. Nevertheless, memory CD4+ T cells are maintained at some level and are important for resistance to secondary infections [285] and for robust recall responses following vaccination [286].

Memory T cells are broadly divided into central memory (TCM) or effector memory (TEM) cells [287]. Similar to naïve T cells, TCM cells are defined by the expression of CCR7 and CD62L [287], which allow their recirculation through lymphoid organs. TCM cells are also highly self-renewing and have a strong proliferative capacity following a secondary infection [288], which is regulated by their increased requirement for antigen during a recall response [289]. Reactivated TCM cells are often polyfunctional, meaning that they produce multiple cytokines [290], particularly IL-2, which promotes secondary expansion [290]. Following secondary expansion in lymphoid organs, TCM efficiently differentiate to effector cells that home to non-lymphoid tissue like the lung.

In contrast with TCM, TEM cells lack CCR7 and CD62L and instead express receptors like CXCR3, CCR4, and CCR5, which promote their homing to sites of inflammation [287]. In fact, TEM typically recirculate through or reside in non-lymphoid tissues [287], including the lung [291]. Unlike TCM, TEM cells do not proliferate strongly after challenge, but instead rapidly exert their effector functions [291]. For example, influenza-specific CD8+ TEM cells rapidly express perforin and granzymes, which allow them to kill target cells within hours of restimulation [292]. Similarly, restimulated CD4+ TEM rapidly express effector cytokines and CD40L, which allow them to activate DCs and B cells, recruit inflammatory cells, and promote antiviral functions [285].

Some TEM cells permanently reside at the original site of antigen encounter, including the lung. These TEM cells are termed resident memory T cells (TRM) [278]. The most stringent identification of TRM cells requires a technique known as parabiosis [293], in which two mice are surgically joined in a way that they share a circulatory system. Recirculating memory T cells, particularly those in lymphoid organs, rapidly equilibrate between the two animals, whereas TRM cells stay in their original host tissue [279]. Using this technique, TRM cells are found in a variety of organs, including the skin, gut, and lung [279], and in some locations, express specific homing and adhesion molecules. For example, skin-homing TRM express CLA and CCR4 [279], whereas gut-homing TRM cells express α4β7 and CCR9 [279]. Although some molecules, such as VLA4 [294], are associated with the retention of TRM in the lung, there is not a unique combination of receptors that identifies lung-homing TRMs [295].

TRM cells in the lung can occupy multiple niches—some reside in the airways and can be recovered by bronchial lavage [296], whereas others reside in the lung parenchyma [297], where they are associated with the airway epithelium. The rapid reactivity of TRM cells and their placement in the lung suggest that they are poised for effector functions following a secondary respiratory infection. In fact, virus-specific TRM in the lung are critically important for immunity to respiratory viruses, including influenza [51,298], RSV [299,300], and Sendai virus [272]. For example, influenza-specific CD8+ TRM cells [51] as well as CD4+ TRM cells [52] mediate resistance to secondary influenza infection. Although TRMs rapidly respond to specific antigen exposure, they also respond to innate stimuli, including cytokines (IL-12, IL-18, and IL-15) and death receptor 3 (DR3) ligands (TL1A) [301,302], in the absence of antigen. Thus, TRM cells specific for one pathogen will also protect against infection with unrelated pathogens. Given that TRM cells are located at sites of infection, it is important that they are not susceptible to infection from those same viruses. This protection is accomplished by the expression of the antiviral gene, IFN-induced transmembrane protein 3 (IFITM3) [303,304], which interferes with the replication of RNA viruses [305].

Some of the mechanisms controlling the differentiation of TRM cells and their maintenance in the lung are known. For example, prolonged antigen presentation in the lung is necessary for the maintenance of influenza-specific CD4+ [298], and CD8+ TRM [306], similar to that observed for TRM cells in other tissues [307]. Influenza-specific CD8+ TRMs also require help from CD4+ T cells, which promote TGFβ-mediated CD103 expression in the lung. CD69 and CD103 are also important for the retention of CD4+ and CD8+ TRM cells in the lung [298,306]. CD8+ TRM cells in the lung typically express both CD69 and CD103, whereas CD4+ TRM in the lung express CD69 and CD11a, but not CD103 [52]. CD103 on CD8+ TRM cells binds to E-cadherin on epithelial cells [308]. The requirement for CD69 on TRM cells is related to the role of sphingosine-1-phosphate (S1P) in T-cell trafficking [309,310]. High levels of S1P in blood normally recruit T cells from peripheral tissues via the lymph [311]. However, CD69 expression on TRM cells interferes with the expression and function of S1PR1 [309], which impairs their ability to sense S1P gradients and supports their retention in the lung [298]. Interestingly, the transcription factor, Kruppel-like factor 2 (KLF2), which promotes S1PR1 expression [312], is lost in TRM cells [312]. The loss of KLF2 also enhances CD69 expression by poorly understood mechanisms [312]. Therefore, the reciprocal regulation of S1PR1 and CD69 is an important mechanism that maintains TRM cells in the lung [313].

Adaptive immunity—B cells and antibodies

Antibodies are the most notable product of B cells and are important for the primary clearance and subsequent resistance to many respiratory viruses [314 ] - see Table 1. Antibodies against respiratory viruses have a variety of functions, depending on their specificity, their isotype, their affinity, and their post-translational modifications [315]. Neutralization is an important function of antibodies that recognize respiratory viruses, and the development of a neutralizing antibody response is the primary goal of most vaccines [316,317]. Antibody-mediated neutralization can occur by steric hindrance or by directly binding to viral spike proteins and blocking virus binding or fusion to the host cell [315,318,319]. Neutralizing antibodies are an important component of immunity against influenza [320], RSV [321,322], coronavirus [323], rhinovirus [324], and Sendai virus [325] infection.

Antibodies also target virions to FcR-expressing phagocytes, such as macrophages [326], DCs [327], and neutrophils [328], in a process known as opsonization [329], which leads to the destruction of virions as well as the presentation of viral antigens to T cells [327]. Antibody-mediated opsonization is enhanced when antigen-bound antibodies fix complement and form immune complexes [330]. These multivalent complexes are recognized by phagocytic cells expressing both FcR and complement receptors [328] and lead to cellular activation and the expression of inflammatory cytokines.

Antibody binding to viral proteins expressed on the surface of host cells also promotes the deposition and proteolytic activation of complement [331]. On cellular targets, the culmination of the complement cascade is the formation of the membrane attack complex, which creates pores in the infected target cells and promotes their lysis [332]. Complement activation also releases bioactive cleavage products [331], including C3a and C5a, which are powerful recruiters of granulocytes, monocytes, and T cells [331]. C5a also stimulates phagocytic activity and leads to the release of cytotoxic granules [333]. Thus, antibody-mediated complement activation is an important component of immunity during respiratory virus infection [334] and in the context of vaccination [335].

Importantly, antibodies of different isotypes are more or less efficient at complement activation [336]. For example, IgM, the first isotype produced after B-cell activation, efficiently activates complement due to its polymeric structure [337]. Although pentameric IgM potently activates complement, hexameric IgM is at least 20-fold more efficient in complement activation [337]. This increased activation is likely due to the hexameric form of C1q [338,339], which initiates the complement cascade. Interestingly, the formation of hexameric complexes of IgG on cell membranes is also critical for complement activation [340]. Although IgA is often produced during viral infection in the upper respiratory tract, it poorly activates complement.

Antibodies bound to infected cells also facilitate recognition by FcR-expressing effector cells, including NK cells [341], macrophages [328], and neutrophils [328]. These cells become activated through various FcγRs and promote the lysis of target cells by releasing cytotoxic granules in a process known as antibody-dependent cellular cytotoxicity (ADCC) [342]. ADCC is an important component of protection against influenza [343,344]. Surprisingly, the so-called broadly neutralizing antibodies that target the conserved stalk regions of influenza HA do not actually neutralize virus in vivo, but instead mediate ADCC on infected cells [345]. A recent study shows that inactivated influenza vaccine resulted in an expansion of both neutralizing and ADCC-mediating antibodies to HA [346]. Some antibody isotypes, notably IgG1 and IgG2 (a and b) strongly bind the activating FcγRIII [342], whereas others like IgG3 poorly bind this receptor in mice [342]. IgM and IgA do not bind FcγR of any type and have their own FcRs [347], which are typically expressed on B cells rather than phagocytic cells. On top of that, post-translational modifications, such as differences in glycosylation strongly influence FcR binding, complement activation, and even antigen binding [342].

Although neutralizing antibodies are valuable in the clearance of primary infection and resistance to secondary infections [348], the antibody response is often directed to a variety of epitopes on multiple viral proteins, many of which are not neutralizing. For example, antibodies are made against every protein in influenza virus [349]. Neutralizing antibodies are primarily directed against epitopes on HA and to a lesser extent on NA [350]. However, non-neutralizing antibodies against NP [351], matrix 1 (M1) [352], and the external domain of M2 (M2e) [353] are also protective to some extent. Some of this non-neutralizing protection can be attributed to the antibody-mediated uptake of antigens that are then presented to T cells [320], which in turn facilitate viral clearance. In addition, proteins like NP are often either expressed on or bound to influenza-infected cells [354,355], which leads to antibody recognition and cellular destruction via the mechanisms described above.

IgM is the first isotype produced following B-cell activation and, although it can mediate the clearance of respiratory viruses on its own [356], it is poorly transported into the airways [348] and has a short half-life in the serum [357]. Nevertheless, an early IgM response to respiratory viruses is necessary for subsequently generating a strong IgG response [358], possibly due to complement activation or feedback through the FcμR [359,360]. Antibodies of the various IgG isotypes are strongly produced following respiratory virus infections and are maintained at high levels in the serum, with a half-life of 4–8 days in mice [357] and 22–23 days in humans [361], due to the neonatal FcR, which recycles IgG back into the serum [362]. Despite the systemic rather than mucosal placement of IgG, it is the best correlate of protection in the context of vaccination against respiratory viruses [314]. In fact, IgG most efficiently protects the lower respiratory tract [62], particularly the alveolar spaces, because it is delivered by transudation across the thin space between alveolar capillaries and alveolar epithelium [363]. In contrast, IgG poorly protects the nasal passages [62].

Unlike IgG, IgA is found at low levels in the serum [357], but at higher concentrations in nasal secretions [364], primarily because it is transported across the mucosal epithelium of the upper respiratory tract via the pIgR [365]. Once IgA is transported from the basolateral surface to the apical surface of epithelial cells, the external domain of pIgR is cleaved and released—still bound to IgA as secretory component [64], which helps protect IgA from proteolytic cleavage in the lumen of the mucosa [64]. IgA antibodies can neutralize respiratory viruses in the nasal passages and even provide non-neutralizing heterosubtypic protection [366,367].

Antigen binding to the B-cell antigen receptor (BCR) promotes B-cell activation and leads to the internalization, processing, and presentation of antigen to Tfh cells in the environment of the germinal center [368,369]. In turn, Tfh cells provide the cytokines and costimulatory molecules necessary for B-cell proliferation and differentiation. Importantly, B cell undergo successive rounds of proliferation, somatic hypermutation, isotype switching, and selection in a process known as affinity maturation [370,371]. High-affinity B cells exit the GC and become either resting memory B cells that do not secrete antibody or long-lived plasma cells that home to the bone marrow and secrete antibody for the life of the individual [371,372]. Long-lived plasma cells are the source of high-affinity neutralizing antibodies in the serum that confer long-term protection against respiratory viruses [373].

Although B cells require help from Tfh cells to form germinal centers and differentiate into memory B cells and long-lived plasma cells, B cells activated by multivalent antigens, such as those in viral capsids or virus envelopes, can also differentiate independently of T-cell help [374]. In T-independent B-cell responses, B cells undergo a brief burst of proliferation before differentiating into short-lived plasmablasts that produce IgM as well as IgG [375]. Without T-cell help, these B cells do not form GCs [371], do not undergo affinity maturation [371], and do not generate memory cells or long-lived plasma cells [371]. Nevertheless, antibodies produced in T-independent responses are effective during acute responses to respiratory viruses [375]. However, since long-lived plasma cells are not produced [375], serum antibody titers rapidly decline and long-term protection is not established.

The differentiation of B cells responding to respiratory viruses is modulated by environmental cues derived from T cells, fibroblastic stromal cells, epithelial cells, and innate cells like DCs and ILCs [373]. For example, B cells responding to RSV differentiate locally in the lung with help of DC-derived BAFF and APRIL [376] . These same cytokines facilitate isotype switching to IgA independently of CD40L [377]. Moreover, IL-5 made by ILC2 cells [378] and TGFβ made by T cells or epithelial cells [373] also help B cell switching to IgA [379], as does the production of retinoic acid by specific subsets of DCs in mucosal tissues [380]. Differences in local isotype switching are also observed following influenza infection [381], as GC B cells in the lung (presumably in iBALT) are divided equally between IgM and IgG-expressing cells, whereas GC B cells in the LN are almost entirely switched to IgG at later times. Moreover, IgA-expressing B cells are not found in either the lung or the LN, but are predominantly found in NALT [381]. Thus, even mucosal lymphoid tissues like NALT and BALT have distinct abilities to produce IgA or other isotypes [26].

Memory B cells are best characterized in human peripheral blood, in which multiple populations can be distinguished using specific markers like CD27, CD38, IgM, and IgG [382]. Unfortunately, CD27 does not distinguish memory B cells in mice [383] and the expression of CD38 is opposite on memory B cells in human (CD38lo) and mouse (CD38hi) [384]. Nevertheless, recent studies show that memory B cells in mice can be divided into subsets based on the expression of CD73, PD-L2, and CD80 [385,386]. Like the distinction between TCM and TEM, some memory B cells are more effective at proliferating and repopulating GCs [387], whereas others are better at differentiating into antibody-secreting cells following secondary encounter with antigen [386,387]. One way of distinguishing BCM from BEM is by the expression of IgM [387]. Memory B cells that have not switched seem better at repopulating GC [387], whereas switched memory B cells more easily differentiate into antibody-secreting cells. CD73 expression also distinguishes the differentiation and proliferative potential of memory B cells [386]. As discussed above, B cells in the LN, NALT, and lung differentially switch during respiratory infection [26,176], resulting in different populations of memory B cells in different locations. However, any differences in the functional activities of these B cells are not yet clear.

Influenza-specific memory B cells are found in the lungs of previously infected mice [54], suggesting that these cells may be lung-resident memory B cells (BRMs), although parabiosis studies have not yet confirmed this possibility. Interestingly, memory B cells in the lung appear to be selected in local GCs (presumably in iBALT) [388], and are more cross-reactive with influenza strains that are unrelated to the infecting virus [388]. This result suggests that B-cell selection uses different mechanisms in different locations—an intriguing, but unverified possibility. In contrast with influenza-specific memory B cells and plasma cells, which seem to be long-lived, coronavirus-specific memory B cells and plasma cells seem to be short-lived [389], even though robust B- and T-cell responses are generated at the time of infection [390]. Memory B cell and plasma cell responses to RSV seem to be similarly short-lived [391]. However the reasons why some viruses fail to elicit long-lived B-cell response are unclear. Nevertheless, it seems that some viruses have mechanisms that limit the development of memory B cells or long-lived plasma cells and prevent successful long-term immunity.

Respiratory viruses have evolved with multiple ways to evade antibody-mediated immunity mechanisms [392]. For example, influenza virus rapidly mutates HA and NA proteins, resulting in new serotypes that are able to evade previously generated neutralizing antibodies—a process known as drift [392]. Moreover, influenza viruses have segmented genomes [392], and can easily recombine with other influenza subtypes to generate viruses expressing nearly unrecognizable HA and NA proteins—a process known as shift [392]. These new viruses often lead to worldwide pandemics, due to lack of preexisting immunity to the new surface proteins [393]. The rapid evolution of influenza is challenging for the development of a ‘universal’ influenza vaccine [348]. The rhinovirus family is similarly diverse and has over 150 serotypes [394]. Moreover, the receptor-binding site of rhinovirus is largely inaccessible to antibodies [395], resulting in an inability to generate a neutralizing antibody response. Interestingly, viruses like RSV have relatively conserved surface proteins [396], but express proteins that modulate the immune response to favor their own survival [397–399]. As discussed above, even though some neutralizing antibodies can be generated against RSV [21], infection seems to primarily elicit a short-lived B-cell response [400], which rapidly fades and leads to susceptibility to secondary infection [401]. Thus, despite the profound long-term success of antibody-generating vaccines against some viruses [402], vaccines against respiratory viruses that are similarly long-lived remain elusive.

Concluding remarks

In summary, our understanding of immunity to respiratory viruses, although impressive, remains incomplete. Many of the basic mechanisms that activate pulmonary DCs and prime virus-specific B and T cells are understood, but the subtle differences in how these mechanisms are manipulated and subverted by particular viruses remains a work in progress. Moreover, although we understand in detail how immune responses work in the context of experimental antigens at systemic sites, these mechanisms are often different in the context of a viral infection of a mucosal site like the respiratory tract. Furthermore, even with our limited understanding how pulmonary immune response are initiated and regulated, we are still awaiting safe and effective vaccines for the majority of respiratory viruses. Thus, a model of respiratory immunity to viral infections remains a work in progress.

Funding

This work was supported by National Institutes of Health (NIH) [grant numbers U19 AI109962, R01 HL069409 and R01 AI097357 (to T.D.R.)]; and [grant number F32 AI120508 (to S.R.A.)].

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • ADCC

    antibody-dependent cellular cytotoxicity

  •  
  • APC

    antigen-presenting cell

  •  
  • APRIL

    a proliferation inducing ligand

  •  
  • AM

    alveolar macrophage

  •  
  • BAFF

    B cell activating factor

  •  
  • BALT

    bronchus-associated lymphoid tissues

  •  
  • BCL6

    B cell lymphoma-6

  •  
  • BCR

    B-cell antigen receptor

  •  
  • BLIMP-1

    B lymphocyte induced maturation protein-1

  •  
  • C3a

    complement 3a

  •  
  • C5a

    complement 5a

  •  
  • CCR

    chemokine C receptor

  •  
  • CD40L

    CD40 ligand

  •  
  • CLA

    cutaneous lymphocyte antigen

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • CTL

    cytolytic effector T cell

  •  
  • DAMP

    damage-associated molecular pattern

  •  
  • DC

    dendritic cell

  •  
  • DR3

    death receptor 3

  •  
  • FLT3

    fms-like tyrosine kinase 3

  •  
  • FOXP3

    forkhead box P3

  •  
  • GC

    germinal center

  •  
  • GM-CSF

    granulocyte macrophage-colony stimulating factor

  •  
  • HA

    hemagglutinin

  •  
  • iBALT

    inducible BALT

  •  
  • ICOS

    inducible T-cell costimulator

  •  
  • IFITM3

    IFN-induced transmembrane protein 3

  •  
  • IFN

    interferon

  •  
  • IL

    interleukin

  •  
  • ILC

    innate lymphoid cell

  •  
  • IRF8

    interferon response factor 8

  •  
  • KLF2

    Kruppel-like factor 2

  •  
  • KLRG1

    killer cell lectin-like receptor G1

  •  
  • LN

    lymph node

  •  
  • M1

    matrix 1

  •  
  • M2e

    external domain of M2

  •  
  • MAVS

    mitochondrial antiviral signaling protein

  •  
  • MBL

    mannan-binding lectin

  •  
  • MCSF

    macrophage colony stimulating factor

  •  
  • MDA5

    melanoma differentiation associated protein

  •  
  • mDC

    migratory DC

  •  
  • MHC

    major histocompatibility complex

  •  
  • Mo-DC

    monocyte-derived DC

  •  
  • MPEC

    memory precursor effector cell

  •  
  • NA

    neuraminidase

  •  
  • NALT

    nasal-associated lymphoid tissue

  •  
  • NK

    natural killer

  •  
  • NS-1

    non-structural-1

  •  
  • NS-2

    non-structural-2

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • PD-1

    programmed death-1

  •  
  • PD-L1

    programmed death ligand 1

  •  
  • PD-L2

    programmed death ligand 2

  •  
  • pDC

    plasmacytoid DC

  •  
  • pIgR

    polymeric Ig-receptor

  •  
  • PPAR

    peroxisome proliferator activated receptor

  •  
  • rDC

    resident DC

  •  
  • RIG-I

    retinoic acid inducible gene 1

  •  
  • RORgt

    RAR-related orphan receptor gamma t

  •  
  • RSV

    respiratory syncytial virus

  •  
  • S1P

    sphingosine-1-phosphate

  •  
  • S1PR1

    sphingosine-1-phosphate receptor 1

  •  
  • SLEC

    short-lived effector cell

  •  
  • STING

    stimulator of interferon genes

  •  
  • TCM

    T-cells central memory

  •  
  • TEM

    T-cells effector memory

  •  
  • Tfh

    T follicular helper

  •  
  • TGF

    transforming growth factor

  •  
  • TH1

    T helper 1

  •  
  • TLR

    toll-like receptor

  •  
  • TNF

    tumor necrosis factor

  •  
  • TNFR

    tumor necrosis factor receptor

  •  
  • TRAIL

    TNF-related apoptosis-inducing ligand

  •  
  • TREG

    T regulatory cell

  •  
  • TRM

    resident memory T cells

  •  
  • VLA4

    very late antigen 4

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